FDA label e9aa11f9-de74-46b1-8f72-90fa1832926f

5 WARNINGS AND PRECAUTIONS Monitoring: Continuously monitor patients while receiving dexmedetomidine HCl in 0.9% sodium chloride injection. ( 5.1 ) Bradycardia and Sinus Arrest: Have occurred in young healthy volunteers with high vagal tone or with different routes of administration, e.g., rapid intravenous or bolus administration. ( 5.2 ) Hypotension and Bradycardia: May necessitate medical intervention. May be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic hypertension, and in the elderly. Use with caution in patients with advanced heart block or severe ventricular dysfunction. ( 5.2 ) Co-administration with Other Vasodilators or Negative Chronotropic Agents: Use with caution due to additive pharmacodynamic effects. ( 5.2 ) Transient Hypertension: Observed primarily during the loading dose. Consider reduction in loading infusion rate. ( 5.3 ) Arousability: Patients can be come aroused/alert with stimulation; this alone should not be considered as lack of efficacy. ( 5.4 ) Tolerance and Tachyphylaxis: Prolonged exposure to dexmedetomidine beyond 24 hours may be associated with tolerance and tachyphylaxis and a dose-related increase in adverse events. ( 5.6 ) 5.1 Drug Administration Dexmedetomidine HCl in 0.9% sodium chloride injection should be administered only by persons skilled in the management of patients in the intensive care or operating room setting. Due to the known pharmacological effects of dexmedetomidine HCl in 0.9% sodium chloride injection, patients should be continuously monitored while receiving dexmedetomidine HCl in 0.9% sodium chloride injection. 5.2 Hypotension, Bradycardia, and Sinus Arrest Clinically significant episodes of bradycardia and sinus arrest have been reported with dexmedetomidine HCl in 0.9% sodium chloride injection administration in young, healthy adult volunteers with high vagal tone or with different routes of administration including rapid intravenous or bolus administration. Reports of hypotension and bradycardia have been associated with dexmedetomidine HCl in 0.9% sodium chloride injection infusion. Some of these cases have resulted in fatalities. If medical intervention is required, treatment may include decreasing or stopping the infusion of dexmedetomidine HCl in 0.9% sodium chloride injection, increasing the rate of intravenous fluid administration, elevation of the lower extremities, and use of pressor agents. Because dexmedetomidine HCl in 0.9% sodium chloride injection has the potential to augment bradycardia induced by vagal stimuli, clinicians should be prepared to intervene. The intravenous administration of anticholinergic agents (e.g., glycopyrrolate, atropine) should be considered to modify vagal tone. In clinical trials, glycopyrrolate or atropine were effective in the treatment of most episodes of dexmedetomidine HCl in 0.9% sodium chloride injection-induced bradycardia. However, in some patients with significant cardiovascular dysfunction, more advanced resuscitative measures were required. Caution should be exercised when administering dexmedetomidine HCl in 0.9% sodium chloride injection to patients with advanced heart block and/or severe ventricular dysfunction. Because dexmedetomidine HCl in 0.9% sodium chloride injection decreases sympathetic nervous system activity, hypotension, and/or bradycardia may be expected to be more pronounced in patients with hypovolemia, diabetes mellitus, or chronic hypertension and in elderly patients. In clinical trials where other vasodilators or negative chronotropic agents were co-administered with dexmedetomidine HCl in 0.9% sodium chloride injection an additive pharmacodynamic effect was not observed. Nonetheless, caution should be used when such agents are administered concomitantly with dexmedetomidine HCl in 0.9% sodium chloride injection. 5.3 Transient Hypertension Transient hypertension has been observed primarily during the loading dose in association with the initial peripheral vasoconstrictive effects of dexmedetomidine HCl in 0.9% sodium chloride injection. Treatment of the transient hypertension has generally not been necessary, although reduction of the loading infusion rate may be desirable. 5.4 Arousability Some patients receiving dexmedetomidine HCl in 0.9% sodium chloride injection have been observed to be arousable and alert when stimulated. This alone should not be considered as evidence of lack of efficacy in the absence of other clinical signs and symptoms. 5.5 Withdrawal Intensive Care Unit Sedation With administration up to 7 days, regardless of dose, 12 (5%) dexmedetomidine HCl in 0.9% sodium chloride injection adult subjects experienced at least 1 event related to withdrawal within the first 24 hours after discontinuing study drug and 7 (3%) dexmedetomidine HCl in 0.9% sodium chloride injection adult subjects experienced at least 1 event 24 to 48 hours after end of study drug. The most common events were nausea, vomiting, and agitation. In adult subjects, tachycardia and hypertension requiring intervention in the 48 hours following study drug discontinuation occurred at frequencies of <5%. If tachycardia and/or hypertension occurs after discontinuation of dexmedetomidine HCl in 0.9% sodium chloride injection supportive therapy is indicated. Procedural Sedation In adult subjects, withdrawal symptoms were not seen after discontinuation of short term infusions of dexmedetomidine HCl in 0.9% sodium chloride injection (<6 hours). 5.6 Tolerance and Tachyphylaxis Use of dexmedetomidine beyond 24 hours has been associated with tolerance and tachyphylaxis and a dose-related increase in adverse reactions [ see Adverse Reactions (6.1) ]. 5.7 Hepatic Impairment Since dexmedetomidine HCl in 0.9% sodium chloride injection clearance decreases with severity of hepatic impairment, dose reduction should be considered in patients with impaired hepatic function [ see Dosage and Administration (2.2 , 2.3 ) ].

6 ADVERSE REACTIONS The following clinically significant adverse reactions are described elsewhere in the labeling: Hypotension, bradycardia and sinus arrest [ see Warnings and Precautions (5.2) ] Transient hypertension [ see Warnings and Precautions (5.3) ] The most common adverse reactions (incidence > 2%) are hypotension, bradycardia, and dry mouth. ( 6.1 ). Adverse reactions associated with infusions greater than 24 hours in duration include ARDS, respiratory failure, and agitation. ( 6.1 ) To report SUSPECTED ADVERSE REACTIONS, contact TAGI Pharma, Inc. at 1-844-668-3942 or FDA at 1-800-FDA-1088 or www.fda.gov/medwatch. 6.1 Clinical Trials Experience Because clinical trials are conducted under widely varying conditions, adverse reactions rates observed in the clinical trials of a drug cannot be directly compared to rates in clinical trials of another drug and may not reflect the rates observed in practice. Most common treatment-emergent adverse reactions, occurring in greater than 2% of patients in both Intensive Care Unit and procedural sedation studies include hypotension, bradycardia, and dry mouth. Intensive Care Unit Sedation Adverse reaction information is derived from the continuous infusion trials of dexmedetomidine HCl in 0.9% sodium chloride injection for sedation in the Intensive Care Unit setting in which 1007 adult patients received dexmedetomidine HCl in 0.9% sodium chloride injection. The mean total dose was 7.4 mcg/kg (range: 0.8 to 84.1), mean dose per hour was 0.5 mcg/kg/hr (range: 0.1 to 6.0) and the mean duration of infusion of 15.9 hours (range: 0.2 to 157.2). The population was between 17 to 88 years of age, 43% ≥65 years of age, 77% male and 93% Caucasian. Treatment-emergent adverse reactions occurring at an incidence of >2% are provided in Table 2. The most frequent adverse reactions were hypotension, bradycardia and dry mouth [ see Warnings and Precautions (5.2) ]. Table 2 Adverse Reactions with an Incidence >2%-Adult Intensive Care Unit Sedation Population <24 hours 26 subjects in the all dexmedetomidine HCl in 0.9% sodium chloride injection group and 10 subjects in the randomized dexmedetomidine HCl in 0.9% sodium chloride injection group had exposure for greater than 24 hours. Adverse Event All dexmedetomidine HCl in 0.9% sodium chloride injection Randomized dexmedetomidine HCl in 0.9% sodium chloride injection Placebo Propofol (N = 1007) (N = 798) (N=400) (N=188) (%) (%) (%) (%) Hypotension 25% 24% 12% 13% Hypertension 12% 13% 19% 4% Nausea 9% 9% 9% 11% Bradycardia 5% 5% 3% 0 Atrial Fibrillation 4% 5% 3% 7% Pyrexia 4% 4% 4% 4% Dry Mouth 4% 3% 1% 1% Vomiting 3% 3% 5% 3% Hypovolemia 3% 3% 2% 5% Atelectasis 3% 3% 3% 6% Pleural Effusion 2% 2% 1% 6% Agitation 2% 2% 3% 1% Tachycardia 2% 2% 4% 1% Anemia 2% 2% 2% 2% Hyperthermia 2% 2% 3% 0 Chills 2% 2% 3% 2% Hyperglycemia 2% 2% 2% 3% Hypoxia 2% 2% 2% 3% Post-procedural Hemorrhage 2% 2% 3% 4% Pulmonary Edema 1% 1% 1% 3% Hypocalcemia 1% 1% 0 2% Acidosis 1% 1% 1% 2% Urine Output Decreased 1% 1% 0 2% Sinus Tachycardia 1% 1% 1% 2% Ventricular Tachycardia <1% 1% 1% 5% Wheezing <1% 1% 0 2% Edema Peripheral <1% 0 1% 2% Adverse reaction information was also derived from the placebo-controlled, continuous infusion trials of dexmedetomidine HCl in 0.9% sodium chloride injection for sedation in the surgical intensive care unit setting in which 387 adult patients received dexmedetomidine HCl in 0.9% sodium chloride injection for less than 24 hours. The most frequently observed treatment-emergent adverse events included hypotension, hypertension, nausea, bradycardia, fever, vomiting, hypoxia, tachycardia, and anemia (see Table 3 ). Table 3 Treatment-Emergent Adverse Events Occurring in >1% Of All Dexmedetomidine-Treated Adult Patients in the Randomized Placebo-Controlled Continuous Infusion <24 Hours ICU Sedation Studies Adverse Event Randomized Dexmedetomidine (N = 387) Placebo (N = 379) Hypotension 28% 13% Hypertension 16% 18% Nausea 11% 9% Bradycardia 7% 3% Fever 5% 4% Vomiting 4% 6% Atrial Fibrillation 4% 3% Hypoxia 4% 4% Tachycardia 3% 5% Hemorrhage 3% 4% Anemia 3% 2% Dry Mouth 3% 1% Rigors 2% 3% Agitation 2% 3% Hyperpyrexia 2% 3% Pain 2% 2% Hyperglycemia 2% 2% Acidosis 2% 2% Pleural Effusion 2% 1% Oliguria 2% <1% Thirst 2% <1% In a controlled clinical trial, dexmedetomidine HCl in 0.9% sodium chloride injection was compared to midazolam for ICU sedation exceeding 24 hours duration in adult patients. Key treatment emergent adverse events occurring in dexmedetomidine or midazolam treated patients in the randomized active comparator continuous infusion long-term intensive care unit sedation study are provided in Table 4. The number (%) of subjects who had a dose- related increase in treatment-emergent adverse events by maintenance adjusted dose rate range in the dexmedetomidine HCl in 0.9% sodium chloride injection group is provided in Table 5. Table 4 Key Treatment-Emergent Adverse Events Occurring in Dexmedetomidine- or Midazolam-Treated Adult Patients in the Randomized Active Comparator Continuous Infusion Long-Term Intensive Care Unit Sedation Study Adverse Event Dexmedetomidine Midazolam (N = 244) (N = 122) Hypotension Hypotension was defined in absolute terms as Systolic blood pressure of <80 mmHg or Diastolic blood pressure of <50 mmHg or in relative terms as ≤30% lower than pre-study drug infusion value. 56% 56% Hypotension Requiring Intervention 28% 27% Bradycardia Bradycardia was defined in absolute terms as <40 bpm or in relative terms as ≤30% lower than pre-study drug infusion value. 42% 19% Bradycardia Requiring Intervention 5% 1% Systolic Hypertension Hypertension was defined in absolute terms as Systolic blood pressure >180 mmHg or Diastolic blood pressure of >100 mmHg or in relative terms as ≥30% higher than pre-study drug infusion value. 28% 42% Tachycardia Tachycardia was defined in absolute terms as >120 bpm or in relative terms as ≥30% greater than pre-study drug infusion value. 25% 44% Tachycardia Requiring Intervention 10% 10% Diastolic Hypertension 12% 15% Hypertension 11% 15% Hypertension Requiring Intervention Includes any type of hypertension. 19% 30% Hypokalemia 9% 13% Pyrexia 7% 2% Agitation 7% 6% Hyperglycemia 7% 2% Constipation 6% 6% Hypoglycemia 5% 6% Respiratory Failure 5% 3% Renal Failure Acute 2% 1% Acute Respiratory Distress Syndrome 2% 1% Generalized Edema 2% 6% Hypomagnesemia 1% 7% The following adverse events occurred between 2 and 5% for dexmedetomidine HCl in 0.9% sodium chloride injection and Midazolam, respectively: renal failure acute (2.5%, 0.8%), acute respiratory distress syndrome (2.5%, 0.8%), and respiratory failure (4.5%, 3.3%). Table 5 Number (%) of Adult Subjects Who Had a Dose-Related Increase in Treatment Emergent Adverse Events by Maintenance Adjusted Dose Rate Range in the Dexmedetomidine HCl in 0.9% Sodium Chloride Injection Group Dexmedetomidine HCl in 0.9% sodium chloride injection (mcg/kg/hr) Adverse Event ≤0.7 Average maintenance dose over the entire study drug administration >0.7 to ≤1.1 >1.1 (N = 95) (N = 78) (N = 71) Constipation 6% 5% 14% Agitation 5% 8% 14% Anxiety 5% 5% 9% Edema Peripheral 3% 5% 7% Atrial Fibrillation 2% 4% 9% Respiratory Failure 2% 6% 10% Acute Respiratory Distress Syndrome 1% 3% 9% Procedural Sedation Adverse reaction information is derived from the two trials for procedural sedation [ see Clinical Studies (14.2) ] in which 318 adult patients received dexmedetomidine HCl in 0.9% sodium chloride injection. The mean total dose was 1.6 mcg/kg (range: 0.5 to 6.7), mean dose per hour was 1.3 mcg/kg/hr (range: 0.3 to 6.1) and the mean duration of infusion of 1.5 hours (range: 0.1 to 6.2). The population was between 18 to 93 years of age, ASA I-IV, 30% ≥65 years of age, 52% male and 61% Caucasian. Treatment-emergent adverse reactions occurring at an incidence of >2% are provided in Table 6. The most frequent adverse reactions were hypotension, bradycardia, and dry mouth [ see Warnings and Precautions (5.2) ]. Pre-specified criteria for the vital signs to be reported as adverse reactions are footnoted below the table. The decrease in respiratory rate and hypoxia was similar between dexmedetomidine HCl in 0.9% sodium chloride injection and comparator groups in both studies. Table 6 Adverse Reactions With an Incidence > 2%—Procedural Sedation Population Adverse Event Dexmedetomidine HCl in 0.9% sodium chloride injection (N = 318) (%) Placebo (N = 113) (%) Hypotension Hypotension was defined in absolute and relative terms as Systolic blood pressure of <80 mmHg or ≤30% lower than pre-study drug infusion value, or Diastolic blood pressure of <50 mmHg. 54% 30% Respiratory Depression Respiratory depression was defined in absolute and relative terms as respiratory rate (RR) <8 beats per minute or > 25% decrease from baseline. 37% 32% Bradycardia Bradycardia was defined in absolute and relative terms as <40 beats per minute or ≤30% lower than pre-study drug infusion value. 14% 4% Hypertension Hypertension was defined in absolute and relative terms as Systolic blood pressure >180 mmHg or ≥30% higher than pre-study drug infusion value or Diastolic blood pressure of >100 mmHg. 13% 24% Tachycardia Tachycardia was defined in absolute and relative terms as >120 beats per minute or ≥30% greater than pre-study drug infusion value. 5% 17% Nausea 3% 2% Dry Mouth 3% 1% Hypoxia Hypoxia was defined in absolute and relative terms as SpO 2 <90% or 10% decrease from baseline. 2% 3% Bradypnea 2% 4% 6.2 Postmarketing Experience The following adverse reactions have been identified during post approval use of dexmedetomidine HCl in 0.9% sodium chloride injection. Because these reactions are reported voluntarily from a population of uncertain size, it is not always possible to reliably estimate their frequency or establish a causal relationship to drug exposure. Hypotension and bradycardia were the most common adverse reactions associated with the use of dexmedetomidine HCl in 0.9% sodium chloride injection during post approval use of the drug. Table 7 Adverse Reactions Experienced During Post-approval Use of Dexmedetomidine HCl in 0.9% Sodium Chloride Injection System Organ Class Preferred Term Blood and Lymphatic System Disorders Anemia Cardiac Disorders Arrhythmia, atrial fibrillation, atrioventricular block, bradycardia, cardiac arrest, cardiac disorder, extrasystoles, myocardial infarction, supraventricular tachycardia, tachycardia, ventricular arrhythmia, ventricular tachycardia Eye Disorders Photopsia, visual impairment Gastrointestinal Disorders Abdominal pain, diarrhea, nausea, vomiting General Disorders and Administration Site Conditions Chills, hyperpyrexia, pain, pyrexia, thirst Hepatobiliary Disorders Hepatic function abnormal, hyperbilirubinemia Investigations Alanine aminotransferase increased, aspartate aminotransferase increased, blood alkaline phosphatase increased, blood urea increased, electrocardiogram T wave inversion, gammaglutamyl transferase increased, electrocardiogram QT prolonged Metabolism and Nutrition Disorders Acidosis, hyperkalemia, hypoglycemia, hypovolemia, hypernatremia Nervous System Disorders Convulsion, dizziness, headache, neuralgia, neuritis, speech disorder Psychiatric Disorders Agitation, confusional state, delirium, hallucination, illusion Renal and Urinary Disorders Oliguria, polyuria Respiratory, Thoracic and Mediastinal Disorders Apnea, bronchospasm, dyspnea, hypercapnia, hypoventilation, hypoxia, pulmonary congestion, respiratory acidosis Skin and Subcutaneous Tissue Disorders Hyperhidrosis, pruritus, rash, urticaria Surgical and Medical Procedures Light anesthesia Vascular Disorders Blood pressure fluctuation, hemorrhage, hypertension, hypotension

<table width="90%" ID="table2"><caption>Table 2 Adverse Reactions with an Incidence &gt;2%-Adult Intensive Care Unit Sedation Population &lt;24 hours <footnote>26 subjects in the all dexmedetomidine HCl in 0.9% sodium chloride injection group and 10 subjects in the randomized dexmedetomidine HCl in 0.9% sodium chloride injection group had exposure for greater than 24 hours.</footnote></caption><col width="20%" align="left" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><col width="20%" align="center" valign="top"/><thead><tr><th styleCode="Rrule Lrule" valign="top" align="left">Adverse Event</th><th styleCode="Rrule" align="left" valign="top">All dexmedetomidine HCl in 0.9% sodium chloride injection</th><th styleCode="Rrule" align="left" valign="top">Randomized dexmedetomidine HCl in 0.9% sodium chloride injection</th><th styleCode="Rrule" align="left" valign="top">Placebo</th><th align="left" valign="top" styleCode="Rrule">Propofol</th></tr><tr><th styleCode="Rrule Lrule"/><th styleCode="Rrule" align="left" valign="top">(N = 1007)</th><th styleCode="Rrule" valign="top" align="left">(N = 798)</th><th styleCode="Rrule" valign="top" align="left">(N=400)</th><th valign="top" align="left" styleCode="Rrule">(N=188)</th></tr><tr><th styleCode="Rrule Lrule" valign="top"/><th styleCode="Rrule" align="left" valign="top">(%)</th><th styleCode="Rrule" valign="top" align="left">(%)</th><th styleCode="Rrule" valign="middle" align="left">(%)</th><th valign="top" align="left" styleCode="Rrule">(%)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Hypotension</td><td styleCode="Rrule">25%</td><td styleCode="Rrule">24%</td><td styleCode="Rrule">12%</td><td styleCode="Rrule">13%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Hypertension</td><td styleCode="Rrule">12%</td><td styleCode="Rrule">13%</td><td styleCode="Rrule">19%</td><td styleCode="Rrule">4%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Nausea</td><td styleCode="Rrule">9%</td><td styleCode="Rrule">9%</td><td styleCode="Rrule">9%</td><td styleCode="Rrule">11%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Bradycardia</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Atrial Fibrillation</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">7%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Pyrexia</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">4%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Dry Mouth</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Vomiting</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Hypovolemia</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">5%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Atelectasis</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">6%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Pleural Effusion</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">6%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Agitation</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Tachycardia</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Anemia</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">2%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Hyperthermia</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">0</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Chills</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">2%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Hyperglycemia</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Hypoxia</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Post-procedural Hemorrhage</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">4%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Pulmonary Edema</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Hypocalcemia</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">0</td><td styleCode="Rrule">2%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Acidosis</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">2%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Urine Output Decreased</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">0</td><td styleCode="Rrule">2%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Sinus Tachycardia</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">2%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Ventricular Tachycardia</td><td styleCode="Rrule">&lt;1%</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">5%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Wheezing</td><td styleCode="Rrule">&lt;1%</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">0</td><td styleCode="Rrule">2%</td></tr><tr><td styleCode="Rrule Lrule">Edema Peripheral</td><td styleCode="Rrule">&lt;1%</td><td styleCode="Rrule">0</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">2%</td></tr></tbody></table>

<table width="90%" ID="table3"><caption>Table 3 Treatment-Emergent Adverse Events Occurring in &gt;1% Of All Dexmedetomidine-Treated Adult Patients in the Randomized Placebo-Controlled Continuous Infusion &lt;24 Hours ICU Sedation Studies</caption><col width="33%" align="left" valign="top"/><col width="34%" align="center" valign="top"/><col width="33%" align="center" valign="top"/><thead><tr><th styleCode="Rrule Lrule">Adverse Event</th><th styleCode="Rrule">Randomized Dexmedetomidine (N = 387)</th><th styleCode="Rrule">Placebo (N = 379)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Hypotension</td><td styleCode="Rrule">28%</td><td styleCode="Rrule">13%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Hypertension</td><td styleCode="Rrule">16%</td><td styleCode="Rrule">18%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Nausea</td><td styleCode="Rrule">11%</td><td styleCode="Rrule">9%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Bradycardia</td><td styleCode="Rrule">7%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Fever</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">4%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Vomiting</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">6%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Atrial Fibrillation</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Hypoxia</td><td styleCode="Rrule">4%</td><td styleCode="Rrule">4%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Tachycardia</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">5%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Hemorrhage</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">4%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Anemia</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">2%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Dry Mouth</td><td styleCode="Rrule">3%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Rigors</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Agitation</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Hyperpyrexia</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Pain</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">2%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Hyperglycemia</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">2%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Acidosis</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">2%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Pleural Effusion</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Oliguria</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">&lt;1%</td></tr><tr><td styleCode="Rrule Lrule">Thirst</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">&lt;1%</td></tr></tbody></table>

<table width="90%" ID="table4"><caption>Table 4 Key Treatment-Emergent Adverse Events Occurring in Dexmedetomidine- or Midazolam-Treated Adult Patients in the Randomized Active Comparator Continuous Infusion Long-Term Intensive Care Unit Sedation Study</caption><col width="34%" align="left" valign="top"/><col width="33%" align="center" valign="top"/><col width="33%" align="center" valign="top"/><thead><tr><th styleCode="Rrule Lrule">Adverse Event</th><th styleCode="Rrule">Dexmedetomidine</th><th styleCode="Rrule">Midazolam</th></tr><tr><th styleCode="Rrule Lrule"/><th styleCode="Rrule">(N = 244)</th><th styleCode="Rrule">(N = 122)</th></tr></thead><tbody><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Hypotension<footnote>Hypotension was defined in absolute terms as Systolic blood pressure of &lt;80 mmHg or Diastolic blood pressure of &lt;50 mmHg or in relative terms as &#x2264;30% lower than pre-study drug infusion value.</footnote></td><td styleCode="Rrule">56%</td><td styleCode="Rrule">56%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Hypotension Requiring Intervention</td><td styleCode="Rrule">28%</td><td styleCode="Rrule">27%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Bradycardia<footnote>Bradycardia was defined in absolute terms as &lt;40 bpm or in relative terms as &#x2264;30% lower than pre-study drug infusion value.</footnote></td><td styleCode="Rrule">42%</td><td styleCode="Rrule">19%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Bradycardia Requiring Intervention</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Systolic Hypertension<footnote ID="foot43">Hypertension was defined in absolute terms as Systolic blood pressure &gt;180 mmHg or Diastolic blood pressure of &gt;100 mmHg or in relative terms as &#x2265;30% higher than pre-study drug infusion value.</footnote></td><td styleCode="Rrule">28%</td><td styleCode="Rrule">42%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Tachycardia<footnote>Tachycardia was defined in absolute terms as &gt;120 bpm or in relative terms as &#x2265;30% greater than pre-study drug infusion value.</footnote></td><td styleCode="Rrule">25%</td><td styleCode="Rrule">44%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Tachycardia Requiring Intervention</td><td styleCode="Rrule">10%</td><td styleCode="Rrule">10%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Diastolic Hypertension<footnoteRef IDREF="foot43"/></td><td styleCode="Rrule">12%</td><td styleCode="Rrule">15%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Hypertension<footnoteRef IDREF="foot43"/></td><td styleCode="Rrule">11%</td><td styleCode="Rrule">15%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Hypertension Requiring Intervention<footnote>Includes any type of hypertension.</footnote></td><td styleCode="Rrule">19%</td><td styleCode="Rrule">30%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Hypokalemia</td><td styleCode="Rrule">9%</td><td styleCode="Rrule">13%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Pyrexia</td><td styleCode="Rrule">7%</td><td styleCode="Rrule">2%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Agitation</td><td styleCode="Rrule">7%</td><td styleCode="Rrule">6%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Hyperglycemia</td><td styleCode="Rrule">7%</td><td styleCode="Rrule">2%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Constipation</td><td styleCode="Rrule">6%</td><td styleCode="Rrule">6%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Hypoglycemia</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">6%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Respiratory Failure</td><td styleCode="Rrule">5%</td><td styleCode="Rrule">3%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Renal Failure Acute</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Acute Respiratory Distress Syndrome</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">1%</td></tr><tr styleCode="Botrule"><td styleCode="Rrule Lrule">Generalized Edema</td><td styleCode="Rrule">2%</td><td styleCode="Rrule">6%</td></tr><tr><td styleCode="Rrule Lrule">Hypomagnesemia</td><td styleCode="Rrule">1%</td><td styleCode="Rrule">7%</td></tr></tbody></table>